Practice Essentials

Acetaminophen has an excellent safety profile when administered in proper therapeutic doses, but hepatotoxicity can occur with misuse and overdose. In the United States, acetaminophen toxicity has replaced viral hepatitis as the most common cause of acute hepatic failure and is the second most common cause of liver failure requiring transplantation.

Essential update: FDA advises prescribers to limit acetaminophen

In January 2014, the FDA issued a statement that combination prescription pain relievers that contain more than 325 mg of acetaminophen per tablet, capsule, or other dosage unit should no longer be prescribed because of a risk of liver damage. Cases of severe liver injury have been reported in patients who took more than the prescribed dose of an acetaminophen-containing product in a 24-hour period, took two or more acetaminophen-containing products simultaneously, or combined alcohol with acetaminophen products.[1, 2]

The FDA also recommends that pharmacists contact prescribers to discuss an alternative when they receive a prescription for a combination product with more than 325 mg of acetaminophen per dosage unit.

Signs and symptoms

Most patients who have taken an overdose of acetaminophen will initially be asymptomatic, as clinical evidence of end-organ toxicity often does not manifest until 24-48 hours after an acute ingestion. To identify whether a patient is at risk, the clinician should determine the time(s) of ingestion, the quantity, and the formulation of acetaminophen ingested.

Minimum toxic doses of acetaminophen for a single ingestion, posing significant risk of severe hepatotoxicity, are as follows:

Adults: 7.5-10 g

Children: 150 mg/kg; 200 mg/kg in healthy children aged 1-6 years

The clinical course of acetaminophen toxicity generally is divided into four phases. Physical findings vary, depending primarily on the level of hepatotoxicity.

Phase 1

0.5-24 hours after ingestion

Patients may be asymptomatic or report anorexia, nausea or vomiting, and malaise

Patients may have continued nausea and vomiting, abdominal pain, and a tender hepatic edge

Hepatic necrosis and dysfunction are associated with jaundice, coagulopathy, hypoglycemia, and hepatic encephalopathy

Acute renal failure develops in some critically ill patients

Death from multiorgan failure may occur

Phase 4: Recovery phase

4 d to 3 wk after ingestion

Patients who survive critical illness in phase 3 have complete resolution of symptoms and complete resolution of organ failure

See Clinical Presentation for more detail.

Diagnosis

The serum acetaminophen concentration is the basis for diagnosis and treatment, even in the absence of symptoms, because of the delay in onset of clinical manifestations of toxicity. The Rumack-Matthew nomogram interprets the acetaminophen plasma concentration in micrograms per mL, as correlated with time in hours after ingestion, to assess hepatotoxicity risk for single acute ingestions of acetaminophen.

Used to interpret plasma acetaminophen values to assess hepatotoxicity risk after a single, acute ingestion

Nomogram tracking begins 4 hours after ingestion (time when acetaminophen absorption is likely to be complete) and ends 24 hours after ingestion

About 60% of patients with values above the "probable" line develop hepatotoxicity

See Workup for more detail.

Management

Gastrointestinal decontamination agents can be used in the emergency department setting in the immediate postingestion time frame. Administer activated charcoal (AC) if the patient is alert and presents, ideally, within 1 hour post ingestion. This time frame can be extended if the patient ingested an acetaminophen-based sustained-release medication or if the ingestion includes agents that are known to slow gastric emptying. Patients with acetaminophen levels below the “possible" line for hepatotoxicity on the Rumack-Matthew nomogram may be discharged home after they are medically cleared.

Admit patients with acetaminophen plasma levels above the possible line on the Rumack-Matthew nomogram for treatment with N -acetylcysteine (NAC). NAC is nearly 100% hepatoprotective when it is given within 8 hours after an acute acetaminophen ingestion, but can be beneficial in patients who present more than 24 hours after ingestion. NAC is approved for both oral and IV administration.

The FDA-approved regimen for oral administration of NAC (Mucomyst) is as follows:

Loading dose of 140 mg/kg

17 doses of 70 mg/kg given every 4 hours

Total treatment duration of 72 hours

The IV formulation of NAC (Acetadote) is commonly used in many institutions for the treatment of acetaminophen ingestion. Use of the IV formulation of NAC is preferred in the following situations:

Altered mental status

GI bleeding and/or obstruction

A history of caustic ingestion

Potential fetal acetaminophen toxicity in a pregnant woman

Inability to tolerate oral NAC because of emesis refractory to proper use of antiemetics

Surgical evaluation for possible liver transplantation is indicated for patients who have severe hepatotoxicity and potential to progress to hepatic failure. Criteria for liver transplantation include the following:

Metabolic acidosis

Renal failure

Coagulopathy

Encephalopathy

See Treatment and Medication for more detail.

Image library

Acetaminophen metabolism is illustrated in the image below.

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Acetaminophen metabolism.

Background

Extensive medical use of acetaminophen began in 1947. Initially in the United States, acetaminophen was available by prescription only. In 1960, this changed to an over-the-counter (OTC) status. The availability of acetaminophen in OTC preparations and the contraindication of aspirin-containing products for pediatric use (due to the association between aspirin and Reye syndrome), have made acetaminophen one of the most commonly used analgesic-antipyretic medication in current pediatric medicine. This widespread use and availability also applies to the adult population, both in the United States and the rest of the world.[3]

Acetaminophen, also known as paracetamol (outside the United States and Canada) and by its chemical name, N -acetyl-p-aminophenol (APAP), is available in more than 200 OTC and prescription medications, either as a single agent or in combination with other pharmaceuticals. Worldwide, acetaminophen is cited as a primary drug in over 50 brand- or trade-name products (eg, Tylenol, Panadol, Tempra, Mapap, FeverAll).

In the United States, 325-mg and 500-mg immediate-release tablets and a 650-mg extended-release preparation marketed for the treatment of arthritis are commonly sold. Combination formulations such as codeine-acetaminophen (Tylenol #3) and oxycodone-acetaminophen (Percocet) are prescribed. Numerous formulations and preparations are readily available, including elixirs, suspensions, tablets (dissolvable (Meltaways) and chewable), caplets, capsules, and paraffin-base rectal suppositories (FeverAll).

Acetaminophen toxicity occurs relatively frequently. In fact, the American Association of Poison Control Centers (AAPCC) reports that acetaminophen is one of the most common pharmaceuticals associated with both intentional and unintentional poisoning and toxicity. Although acetaminophen has an excellent safety profile when administered in proper therapeutic doses, hepatotoxicity can occur with misuse and overdose.

Overdose with acetaminophen can occur at any age. A therapeutic misadventure typically occurs in children, younger than 1 year, when their caregivers give incorrect doses of a medication containing acetaminophen. Accidental poisoning (unintentional ingestion) can occur in toddlers and young children with unsupervised access to medications. Older patients (eg, teenagers and adults) may overdose with intent to do self-harm.[4]

While acetaminophen toxicity is particularly common in children, adults have accounted for most of the serious and fatal cases.[4] Acetaminophen toxicity is the most common cause of hepatic failure requiring liver transplantation in Great Britain. In the United States, acetaminophen toxicity has replaced viral hepatitis as the most common cause of acute hepatic failure and is the second most common cause of liver failure requiring transplantation.

In an attempt to decrease this potential for acetaminophen toxicity in the United States, a number of pharmaceutical regulatory changes have been introduced. In 2009, the US Food and Drug Administration (FDA) required that nonprescription and prescription APAP-containing medications provide information regarding the risks of acetaminophen-induced hepatotoxicity.[5, 6] In addition, the FDA has considered the removal of acetaminophen from some popular analgesic combination products (eg, hydrocodone-acetaminophen [Vicodin]) and possibly decreasing the recommended maximum daily dose. The FDA is also addressing other changes to acetaminophen-based medications, including the following:

In January 2011, the FDA announced that it was asking manufacturers of prescription acetaminophen combination products to limit the maximum amount of APAP in these products to 325 mg per tablet, capsule, or other dosage unit.[7] And in January 2014, the FDA issued a statement advising that combination prescription pain relievers that contain more than 325 mg of acetaminophen per tablet, capsule, or other dosage unit should no longer be prescribed because of a risk for liver damage.[1, 2]

Unrelated to dosage, another announcement from the FDA in August 2013 advised that anyone who has a skin reaction, such as the development of a rash or blister, while taking acetaminophen should stop using the drug and seek immediate medical care. A review of the medical literature showed the painkiller poses the risk for 3 rare but potentially fatal skin disorders — Stevens-Johnson syndrome, toxic epidermal necrolysis, and acute generalized exanthematous pustulosis.[8, 9]

An intravenous (IV) formulation of acetaminophen (Ofirmev) was approved by the FDA in 2011 for inpatient use in children older than 2 years to treat fever and pain.[10] Although this article focuses on single acute ingestions of oral formulations, iatrogenic medication errors with IV acetaminophen have caused hepatotoxicity.[11] The evaluation and treatment approach for an IV acetaminophen overdose is similar to that of an oral overdose.

Clinical evidence of end-organ toxicity is often delayed 24-48 hours after an acute ingestion of acetaminophen occurs. Consequently, the diagnosis of potential acetaminophen toxicity is based on obtaining a history of acetaminophen ingestion and confirming a potentially toxic blood level. The modified Rumack-Matthew nomogram, (the acetaminophen toxicity nomogram or acetaminophen nomogram), is used to interpret plasma acetaminophen concentrations relative to time post ingestion to assess for the hepatotoxicity risk in patients. See Workup.

Oral activated charcoal avidly adsorbs acetaminophen. This gastrointestinal (GI) decontaminant can afford significant treatment benefit if administered to the patient within 1 hour post ingestion, or later if the ingestion involves an agent that delays gastric emptying or slows GI motility. N -acetylcysteine (NAC), or acetylcysteine, is an extremely effective antidote for acetaminophen-induced hepatotoxicity due to an acute overdose, especially if administered within 8-10 hours after ingestion.[12] See Treatment and Medication.

Pathophysiology

Oral acetaminophen is rapidly absorbed from the stomach and small intestine. The serum concentration peaks 1-2 hours post ingestion. Therapeutic levels are 5-20 µg/mL (33-132 µmol/L). Peak plasma levels occur within 4 hours after ingestion of an overdose of an immediate-release preparation. Co-ingestion with drugs that delay gastric emptying (eg, opiates, anticholinergic agents) or ingestion of an acetaminophen extended-release formulation may result in peak serum levels to be achieved more than 4 hours post ingestion.

Generally, the elimination half-life of acetaminophen is 2 hours (range 0.9-3.25 h). In patients with underlying hepatic dysfunction, the half-life can last as long as 17 hours post ingestion.

Acetaminophen is primarily metabolized by conjugation in the liver to nontoxic, water-soluble compounds that are eliminated in the urine. In acute overdose or when the maximum daily dose is exceeded over a prolonged period, metabolism by conjugation becomes saturated, and excess APAP is oxidatively metabolized by the CYP enzymes (CYP2E1, 1A2, 2A6, and 3A4) to the hepatotoxic reactive metabolite, N -acetyl-p -benzoquinoneimine (NAPQI).

NAPQI has an extremely short half-life and is rapidly conjugated with glutathione, a sulfhydryl donor, and is then renally excreted. Under conditions of excessive NAPQI formation or a reduction in glutathione stores by approximately 70%, NAPQI covalently binds to the cysteinyl sulfhydryl groups of hepatocellular proteins, forming NAPQI-protein adducts. This causes an ensuing cascade of oxidative damage and mitochondrial dysfunction. The subsequent inflammatory response propagates hepatocellular injury and death. Necrosis primarily occurs in the centrilobular (zone III) region, owing to the greater production of NAPQI by these cells. Thus, the production of NAPQI, in excess of an adequate store of conjugating glutathione in the liver tissue, is associated with hepatocellular damage, necrosis, and hepatic failure. Similar enzymatic reactions occur in extrahepatic organs, such as the kidney, and can contribute to some degree of extrahepatic organ dysfunction.

Currently, the maximum recommended daily dose of APAP is 75 mg/kg for children and 4 g for adults. The minimum hepatotoxic dose of APAP as a single acute ingestion is 150 mg/kg for a child and 7.5-10 g for an adult.

The ingested amount of APAP at which toxicity may occur may be less in the setting of chronic ethanol use, compromised nutritional states, fasting, or viral illness with dehydration. Co-ingestions of substances or medications known to induce the activity of the APAP-metabolizing cytochrome P (CYP) oxidative enzymes also increase the risk of hepatotoxicity; however, when proper dosing recommendations are followed, the risk of hepatotoxicity is extremely small.

The antidote for acetaminophen poisoning, NAC, is theorized to work through a number of protective mechanisms. Since NAC is a precursor of glutathione, it increases the concentration of glutathione available for the conjugation of NAPQI. NAC also enhances sulfate conjugation of unmetabolized APAP, functions as an anti-inflammatory and antioxidant, and has positive inotropic effects.

In addition, NAC increases local nitric oxide concentrations and promotes microcirculatory blood flow, enhancing local oxygen delivery to peripheral tissues. The microvascular effects of NAC therapy are associated with a decrease in morbidity and mortality, even when NAC is administered in the setting of established hepatotoxicity.

NAC is maximally hepatoprotective when administered within 8 hours of an acute acetaminophen ingestion. When indicated, however, NAC should be administered, regardless of the time since the overdose. Therapy with NAC has been shown to decrease mortality rates in late-presenting patients with fulminant hepatic failure, even in the absence of measurable serum APAP levels.

See the image below.

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Acetaminophen metabolism.

Etiology

Production of NAPQI by the CYP system in amounts greater than can be conjugated with existing stores of glutathione is the cause of liver toxicity in acetaminophen overdose. Susceptibility is enhanced by conditions that reduce glutathione stores in the body, which include the following:

In addition, the production of NAPQI (and thus the risk of hepatocellular injury) is increased by activation of the hepatic cytochrome system. Agents and medications that induce CYP enzyme activity are numerous, and include some of the following:

Ethanol ingestion

Tobacco smoking

Isoniazid (INH)

Rifampin

Phenytoin

Phenobarbital

Barbiturates

Carbamazepine

Trimethoprim-sulfamethoxazole (TMP-SMZ)

Zidovudine

Maximum acetaminophen dosages

Historically, the maximum daily adult dose of acetaminophen is 4 g, with a recommended dosage of 352-650 mg every 4-6 hours or 1 g every 6 hours. In 2012, dosage recommendations changed the maximum daily dose for adults to 3 g, with no more than 650 mg every 6 hours, as needed. For children younger than 12 years and/or less than 50 kg in weight, the maximum daily dose is 75 mg/kg, with a recommended dosage of 10-15 mg/kg every 4-6 hours as needed and no more than 5 doses per 24-hour period. Because of absorption differences, weight-based rectal suppository dosing for children is higher, at 15-20 mg/kg per dose, using the same time interval as for oral acetaminophen.

Minimum toxic acetaminophen dosages

In adults, the minimum toxic dose of acetaminophen for a single ingestion is 7.5-10 g. In children, the minimum toxic dose of APAP for a single acute ingestion is 150 mg/kg.

In healthy children aged 1-6 years, medical toxicologists recommend increasing this threshold to 200 mg/kg. Children in this age group are less susceptible to hepatotoxicity from acute acetaminophen poisoning. Differences in medication metabolism within this age group and a relatively larger hepatic mass (ie, ratio of organ weight to total body weight) may both play roles in more efficiently detoxifying and eliminating NAPQI.

Toxic acetaminophen dosages

In adults, an acute ingestion of more than 150 mg/kg or 12 g of acetaminophen is considered a toxic dose and poses a high risk of liver damage. In children, acute ingestion of 250 mg/kg or more poses significant risk for acetaminophen-induced hepatotoxicity. Children who ingest more than 350 mg/kg are at great risk for severe hepatotoxicity if not properly treated.

In June 2009, the FDA announced requirements for nonprescription and prescription medications to provide new information regarding acetaminophen–induced hepatotoxicity.[13, 14, 15] The FDA addressed the possibility of removing acetaminophen from some popular analgesic combination products (eg, hydrocodone-acetaminophen [Vicodin]) and/or lowering the maximum cited daily dose of acetaminophen. The following concerns were also addressed:

In January 2011, the FDA asked manufacturers of prescription acetaminophen combination products to limit the maximum amount of APAP in these products to 325 mg per tablet, capsule, or other dosage unit.[7] And in January 2014, the FDA issued a statement advising doctors to stop prescribing combination prescription pain relievers that contain more than 325 mg of acetaminophen per tablet, capsule, or other dosage unit.[1, 2]

In addition, a proposal moving to one standard concentration (160 mg/5 mL) of liquid acetaminophen medication for infants and children was announced in May 2011. Until recently, mainly 2 concentrations of OTC APAP formulations were available: 80 mg/0.8 mL (Infant Concentrated Drops) and 160 mg/5 mL (Children's Liquid Suspension or Syrup). Creating one standard concentration would minimize confusion of administration of acetaminophen preparations by caregivers.[16]

The hope is that establishing these formulation changes will help reduce the occurrence of acetaminophen overdosing for both children and adults and decrease the number of acute ingestions that cause hepatotoxicity, leading to acute liver failure.[7]

Chronic acetaminophen toxicity

Chronic acetaminophen toxicity has been recognized in pediatric patients. This condition occurs in young, febrile children with reduced oral intake who are treated with repeated high doses of acetaminophen to relieve their symptoms. As a reference, the 24-hour dosage of acetaminophen for children should not exceed 75 mg/kg/d.

In chronic acetaminophen toxicity, the role of fasting, reduced glutathione stores, and enhanced metabolism remains unclear. Risk factors for chronic acetaminophen toxicity include the following[17] :

Epidemiology

Acetaminophen toxicity is the most common cause of hepatic failure requiring liver transplantation in Great Britain. In the United States, acetaminophen toxicity has replaced viral hepatitis as the most common cause of acute hepatic failure and is the second most common cause of liver failure requiring transplantation. Although acetaminophen toxicity is particularly common in children, adults have accounted for most of the serious and fatal cases.[4]

Prognosis

With aggressive supportive care and antidotal therapy, the mortality rate associated with acetaminophen hepatotoxicity is less than 2%. If correctly treated in a timely manner, most patients do not suffer significant sequelae; patients who survive are expected to have return of normal hepatic function. In case series, fewer than 4% of patients who suffer severe hepatotoxicity develop hepatic failure; fatalities or the need for liver transplantation occurs in less than half of these patients.

Chronic ethanol use or diminished nutritional status may increase the risk for morbidity because these conditions result in deficient glutathione stores and a subsequent inability to conjugate and detoxify NAPQI. Use of substances that induce the activity of the APAP-metabolizing CYP enzymes may increase the risk of morbidity by enhancing the production of NAPQI (see Etiology).

Pediatric patients younger than 6 years appear to fare better than adults after acute acetaminophen poisoning, perhaps owing to their greater capacity to conjugate APAP through sulfation, enhanced detoxification of NAPQI, or greater glutathione stores. However, as no controlled studies have supported an alternative pediatric-specific therapy, treatment in children is the same as in adults.

A number of screening measurements have been studied as prognostic indicators after acetaminophen ingestion. The most widely used predictors are the King’s College Criteria, which have been well-validated to predict poor outcome and need for liver transplantation after an isolated acetaminophen overdose. The criteria consist of the following laboratory abnormalities; any serological or clinical finding should prompt urgent transplantation consultation:

Arterial pH less than 7.30 after fluid resuscitation

Creatinine level greater than 3.4 mg/dL

Prothrombin time (PT) greater than 1.8 times control or greater than 100 seconds, or International Normalized Ratio (INR) greater than 6.5

Grade III or IV encephalopathy

Another prognostic screening tool that has been studied in regard to predicting the need for liver transplantation is the Acute Physiology and Chronic Health Evaluation II (APACHE II) score completed on the patient’s first inpatient hospital stay. In one study, the APACHE II score was found to be accurate, but cumbersome to apply.[18]

Additional early predictors include changes in serum phosphate levels, which indirectly represent the balance between the development of renal failure and hepatic regeneration. Serum phosphate concentrations greater than 1.2 mmol/L measured at 48-96 hours after overdose were sensitive and specific for increased mortality.[19]

Finally, elevations in blood lactate levels have been studied as prognostic indicators after acute acetaminophen overdose.[20] Blood lactate levels greater than 3.5 mmol/L before fluid resuscitation or greater than 3 mmol/L after fluid resuscitation were found to be sensitive and specific indicators of survival. When compared to the King’s College Criteria, there was no significant time difference to clearly identify patients who required transplantation.

Patient Education

Acetaminophen is commonly considered an innocuous OTC drug; hence, it is extremely important to advise patients of the potential risks associated with its inappropriate use. Inform parents and caregivers that acetaminophen, although safe when dosed properly, can cause significant harm if misused.

Educate parents in the proper dosing for children and the danger associated with misusing various acetaminophen preparations of different concentrations (eg, infant suspension vs pediatric elixir, pediatric vs adult suppositories). Currently, one standard concentration (160 mg/5 mL) of liquid acetaminophen medication is available for infants and children. Before 2011, OTC APAP formulations for infants and children were 80 mg/0.8 mL (Infant Concentrated Drops) and 160 mg/5 mL (Children's Liquid Suspension or Syrup). Despite the change to one standard formulation, the older concentrations (80 mg/0.8 mL) of infant acetaminophen may still be found in some homes. If an older APAP product is to be used, confirm the correct concentration of infant acetaminophen with the caregiver to prevent therapeutic error.[16]

Parents should always be given clear dose and formulation instructions based on the age and weight of the child. Preferably, caregivers should use the dropper or syringe-measuring tool that accompanies the product. Parents must be instructed to carefully examine the labels of OTC medications that may contain acetaminophen in combination formulations.

Educate patients and caregivers about the increased potential for renal toxicity associated with concurrent acetaminophen and nonsteroidal anti-inflammatory drug (NSAID) analgesic use or with chronic ethanol use.

Parents and caregivers must ensure proper storage of medications within the home. This is critical in order to prevent unsupervised access to drugs or other toxic substances by children. The goal is to minimize the risk of an unintentional ingestion of a potentially toxic agent.

Supply parents and caregivers with contact information for their local Poison Control Center and the telephone number for the toll-free Poison Help Line (1-800-222-1222). In addition, McNeil Pharmaceuticals (makers of the brand name “Tylenol” products) sponsors a toll-free number through the Rocky Mountain Poison and Drug Center, 1-800-525-6115, available 24 hours/d, for further consultation and guidance.[21]

For patient education information, see Acetaminophen (Tylenol) Poisoning and Poisoning. The US Food and Drug Administration (FDA) provides patient and caregiver education resources through its Consumer Health Information Website.[22, 7]

History

Most patients who have taken an overdose of acetaminophen will initially be asymptomatic, as clinical evidence of end-organ toxicity often does not manifest until 24-48 hours after an acute ingestion.

Because antidotal therapy is most effective when initiated within 8 hours after an ingestion, it is important to obtain an accurate history of the time(s) of ingestion, the quantity, and the formulation of acetaminophen ingested. Knowledge of the maximum recommended and minimum toxic dosages, as well as underlying conditions that increase susceptibility, can help the clinician determine the risk for toxicity (see Etiology). In addition, the history should include any co-ingestants, such as salicylates or medications, which may delay acetaminophen absorption (eg, anticholinergic drugs or opioids).

Physical Examination

The clinical course of acetaminophen toxicity generally is divided into 4 phases (also referred to in the medical literature as stages). Physical findings vary, depending primarily on the level of hepatotoxicity.

In phase 1 (0.5-24 hours after ingestion), patients may be asymptomatic or report anorexia, nausea or vomiting, and malaise. Physical examination may reveal pallor, diaphoresis, malaise, and fatigue. It is during this phase that patients are most likely to be given an APAP-containing medication to alleviate their nonspecific symptoms.

Phase 3 (72-96 h after ingestion), is also called the hepatic phase. Patients may have continued nausea and vomiting, abdominal pain, and a tender hepatic edge. Hepatic necrosis and dysfunction are associated with jaundice, coagulopathy, hypoglycemia, and hepatic encephalopathy. Acute renal failure develops in some critically ill patients. Death from multiorgan failure may occur.

Phase 4 is the recovery phase (4 d to 3 wk after ingestion). Patients who survive critical illness in phase 3 have complete resolution of symptoms and resolution of organ failure. Clinical recovery may take up to 21 days; however, complete hepatic histologic recovery requires several months.

Approach Considerations

The serum acetaminophen (APAP) concentration is the basis for diagnosis and treatment, even in the absence of symptoms, because of the delay in onset of clinical manifestations of toxicity. After a single ingestion, N -acetylcysteine (NAC) therapy is guided by the serum APAP concentration. An APAP level 4 hours post ingestion of greater than 150 mcg/mL (>993 µmol/L) reflects possible toxicity.

The Rumack-Matthew nomogram uses the serum acetaminophen level, correlated with time after ingestion, to assess hepatotoxicity risk for single acute ingestions of acetaminophen. It should not be used to evaluate chronic or repeated exposures. Diagnosing chronic acetaminophen toxicity can be difficult, because the patient's presentation may appear to reflect the initial illness. In these situations, consult a poison control center or a medical toxicologist to discuss treatment strategies.

Obtain an electrocardiogram (ECG) in order to exclude the presence of cardioactive substances/co-ingestants. Order a serum salicylate level to properly address co-concerns for salicylate poisoning.

Obtain liver function tests (LFTs). Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels begin to rise within 24 hours after an acute ingestion and peak at about 72 hours. In severe overdose, transaminase elevation can be detected as early as 12-16 hours post-ingestion. Toxicity is defined as serum AST or ALT levels greater than 1000 IU/L. A rapid progression of transaminase values to 3000 IU/L or higher reflects worsening hepatotoxicity. Include bilirubin and alkaline phosphatase levels.

Prothrombin time (PT) and international normalized ratio (INR) should be measured and followed closely if hepatic dysfunction and liver failure develop, as they indicate impaired hepatic synthetic function. Abnormalities in these laboratory components are predictors of mortality. Obtain a blood type and cross-match in the event of coagulopathy and active bleeding, to have available for need of blood products.

Obtain a serum glucose level to assess for hypoglycemia (as due to hepatic injury).

Renal function tests (ie, electrolyte, blood urea nitrogen [BUN], and creatinine levels) can reveal evidence of renal failure, which often occurs with hepatic failure.[23] An elevated serum creatinine level is also a predictor of mortality. Urinalysis to check for proteinuria and hematuria helps in diagnosing acute tubular necrosis. Renal injury becomes apparent 2-3 days after an acute acetaminophen ingestion (phase 2). Rarely, renal failure can occur independently of hepatic failure.[24] One study indicated that this is more likely to occur in persons who have history of ethanol abuse.

Assess for pancreatic injury by obtaining lipase and amylase levels, especially if the patient has evidence of clinically significant hepatotoxicity and complaints of severe abdominal pain.

Abdominal ultrasonography is a noninvasive tool that may reveal mild hepatic enlargement or renal abnormalities, as well as assess for involvement of other abdominal organs (eg, pancreatic tissue).

In females of childbearing age, obtain serum levels of human chorionic gonadotropin (hCG).[25] If positive, ultrasound can confirm gestational age of the fetus. Acetaminophen crosses the placenta, and the fetal liver is able to elaborate the hepatotoxic metabolite of APAP, N -acetyl-p-benzoquinone imine (NAPQI) by 14 weeks’ gestation. Delayed antidotal treatment in pregnant women has been associated with fetal loss. For concern of severe hepatic insult, perform an arterial blood gas evaluation. A pH of less than 7.3 after fluid resuscitation is a laboratory indicator predictive of mortality. Serum phosphate values have also been used as an early predictor of outcome in severe acetaminophen-induced hepatotoxicity; however, these values are not considered strong prognostic indicators to guide antidotal treatment.[19]

Presence of mental status changes or clinical signs of encephalopathy warrant obtaining serum ammonia levels. An arterial sample is best. Also consider computed tomography (CT) scanning of the brain in patients with altered mental status. This study may reveal cerebral edema in patients with late presentation and encephalopathy (grade III or IV). Additional neuroimaging with magnetic resonance imaging (MRI) may be indicated to further define cerebral changes.

Key laboratory findings during the first 3 phases of acetaminophen hepatotoxicity are as follows:

Rumack-Matthew Nomogram

The Rumack-Matthew nomogram (the acetaminophen toxicity nomogram or acetaminophen nomogram), is used to interpret plasma acetaminophen values to assess hepatotoxicity risk in patients. It was developed for single, acute ingestions of acetaminophen and is based on observational data from patients who overdosed and who did not receive antidote therapy. See the image below.

The upper line of the nomogram is the “probable” line, also known as the Rumack-Matthew line. About 60% of patients with values above this line develop hepatotoxicity. The lower line on the nomogram is the “possible” line, which was subsequently added later as per request of the FDA. The possible line, also known as the “treatment” line, gives a 25% margin of error to allow for variations in measurements of the acetaminophen plasma concentration (µg/mL or µmol/L [SI units]) or for uncertainty regarding the time of ingestion.

The nomogram cannot be used if the patient presents more than 24 hours after ingestion or has a history of multiple acetaminophen ingestions. Its reliability decreases for ingestions of extended-release acetaminophen formulations or for co-ingestions of acetaminophen with anticholinergics or opioids.

Anion Gap

A high anion gap (see the Anion Gap calculator) may be found in clinically ill patients who present soon after acetaminophen ingestion; the etiology is hypothesized to be an elevated serum lactate level.[26] In critically ill patients, an elevated serum lactate value is a laboratory predictor of mortality. However, this laboratory result is not predictive of clinical course or outcome if patients are treated with proper medical care.

NAPQI-Protein Adducts

Serum concentrations of NAPQI-protein adducts have been measured as evidence of acetaminophen–induced hepatotoxicity.[27] The peak serum concentrations of NAPQI adducts correlate with peak AST and ALT concentrations, and they may be diagnostic of APAP-induced hepatotoxicity in late-presenting patients with acute liver failure of unknown etiology.

However, the measurement of NAPQI-protein adducts is not available in real-time clinical practice and requires the resources of specialized laboratories. These laboratory measurements should not guide treatment decisions.

Histologic Features

Patients who reach phase 4 hepatotoxicity have hepatic histologic changes. These changes can range from cytolysis to centrilobular necrosis. Centrilobular hepatic tissue injury is due to the increased concentration of CYP2E1 enzymes in this cellular area, hence the high production of NAPQI. Improvement and recovery of these histologic changes takes longer than clinical recovery (about 3 mo).

Approach Considerations

Initial appropriate supportive care is essential in acetaminophen poisoning. Immediate assessment of the patient's airway, breathing, and fluid status (ie, ABCs) is critical before treatment for suspected acetaminophen overdose is initiated. In addition, assessing for other potential life-threatening co-ingestions (eg, salicylate) is very important.

Administer activated charcoal (AC) if the patient has a stable mental and clinical status and presents to the emergency department within 1 hour of ingestion. Draw a 4-hour serum acetaminophen concentration to determine the risk for hepatotoxicity, plot this value using the Rumack-Matthew nomogram.

Patients with acetaminophen levels below the “possible” line for hepatotoxicity on the Rumack-Matthew nomogram may be discharged home after they are medically cleared. If the ingestion occurred with intent to do self-harm, a thorough psychosocial, psychological and/or psychiatric evaluation is indicated before the patient can be discharged safely from the medical care facility.

Admit patients with acetaminophen plasma levels above the possible line on the Rumack-Matthew nomogram for treatment with N -acetylcysteine (NAC). Treat patients with evidence of hepatic failure, metabolic acidosis, coagulopathy, and/or encephalopathy in an intensive care unit (ICU). Transfer patients with evidence of clinically significant hepatotoxicity to a medical facility with intensive care support and organ transplant services.

More important than GI decontamination after APAP ingestion is the early administration of NAC.[28] NAC is nearly 100% hepatoprotective when it is given within 8 hours after an acute acetaminophen ingestion. Guidelines from the American College of Emergency Physicians recommend the use of NAC to treat acute acetaminophen overdose in patients with either possible or probable risk for hepatotoxicity, according to the Rumack-Matthew nomogram, ideally within 8-10 hours post ingestion.[29]

Because of the benign nature of NAC, and the risk of adverse effects from acetaminophen toxicity, NAC should be given even if the history is unclear but a potentially toxic acetaminophen ingestion is suspected. NAC should be administered while awaiting a serum APAP level if the patient presents close to or later than 8 hours after an acute ingestion, or if the patient is pregnant.

A late presentation should not preclude NAC administration if the history or presentation suggests potential toxicity.[30] Failure to administer NAC because of late presentation is considered medically and legally inappropriate.

Surgical evaluation for possible liver transplantation is indicated for patients who have severe hepatotoxicity and potential to progress to hepatic failure. Criteria for liver transplantation include the following:

Gastric Decontamination

Oral AC avidly adsorbs acetaminophen and may be administered if the patient presents within 1 hour after ingesting a potentially toxic dose. AC should notbe administered if the patient is mentally compromised and does not have an intact or protected airway.[31]

Oral AC may be of benefit longer than 1 hour after the ingestion if the ingestion involves an agent that delays gastric emptying or slows gastrointestinal (GI) motility. In one case series, oral AC administered with NAC 4 hours after ingestion was shown to be effective in reducing the incidence of transaminitis after toxic APAP ingestion.[30] However, it is well documented that the effectiveness of oral AC diminishes over time, especially beyond 60 minutes after a toxic ingestion.

Oral N-Acetylcysteine

The oral formulation of NAC (Mucomyst) is the drug of choice for the treatment of acetaminophen overdose. GI decontamination with activated charcoal prior to starting NAC therapy does not change the therapeutic schedule for treatment. The FDA-approved dosage regimen for oral NAC starts with a loading dose of 140 mg/kg, followed by 17 doses, each at 70 mg/kg, given every 4 hours. The total duration of the treatment course is 72 hours.[21]

A national multicenter study found that oral NAC is safe and effective for as long as 24 hours after a toxic ingestion.[32] Treatment with oral NAC effectively prevented hepatotoxicity, regardless of the initial serum acetaminophen level, if it was started within 8 hours of the ingestion. NAC's treatment effectiveness did not depend on whether it was started 0-4 or 4-8 hours after ingestion.[32]

Intravenous N-Acetylcysteine

In 2004, the FDA approved an intravenous (IV) formulation of NAC (Acetadote) for use in adults. In February 2006, this FDA approval was modified to include children (patients < 40 kg). IV NAC is the common formulation used in many hospitals. Additional indications for IV administration of NAC also include the following:

Altered mental status

GI bleeding and/or obstruction

A history of caustic ingestion

Potential fetal acetaminophen toxicity in a pregnant woman

Inability to tolerate oral NAC because of emesis refractory to proper use of antiemetics

Pharmaceutical guidelines for IV NAC administration depend on the patient's body weight and/or on whether the ingestion is acute or chronic. Continuous IV infusion is recommended for acute ingestion, as follows:

Loading dose: 150 mg/kg IV; mix in 200 mL of 5% dextrose in water (D5W) and infuse over 1 h

Dose 2: 50 mg/kg IV in 500 mL D5W over 4 h

Dose 3: 100 mg/kg IV in 1000 mL D5W over 16 h

In patients who weigh more than 100 kg, limited data suggest a loading dose of 15,000 mg infused IV over 1 hours, then a first maintenance dose of 5,000 mg IV over 4 hours and a second maintenance dose of 10,000 mg over 16 hours.

Intermittent IV infusion may be considered for late-presenting or chronic ingestion. A loading dose of 140 mg/kg IV (diluted in 500 mL D5W) is infused over 1 h. Maintenance doses of 70 mg/kg IV are given every 4 hours for at least 12 doses (dilute each dose in 250 mL of D5W and infuse over a minimum of 1 hour).

Adverse side effects associated with the IV administration include flushing, pruritus, and rash (seen in about 15% of patients). Stopping the infusion, administering an antihistamine, and restarting NAC at a slower infusion rate remedy these adverse effects. Bronchospasm and hypotension can occur; however, these adverse effects are rare (< 2% of patients).[33]

NAC and AC Interaction and Administration

Early administration of NAC is more important than GI decontamination with oral AC in cases of acetaminophen overdose. Despite binding to NAC, AC adsorbs APAP more avidly. Therefore, although the administration of AC may decrease the bioavailability of oral NAC, this decrease is clinically inconsequential. Importantly, AC administration may prevent significant APAP absorption from the GI tract and obviate the need for NAC.[34]

Oral NAC administration may be staggered with AC administration in the rare cases where the patient needs multiple doses of AC for the treatment of a co-ingestant.[35] Treatment with intravenous NAC administration is preferable in this situation.

Consider and evaluate for possible co-ingestants and consider the possible effects of decreased GI motility on the absorption of APAP; the predictive value of the treatment nomogram may be less reliable in these situations. Therefore, in the absence of good data on multidrug ingestions or co-ingestions involving APAP, administer NAC as early as possible and consult the regional poison control center for guidance on a treatment regimen.

Delayed Presentation

If a patient presents 8-24 hours or later after an acute ingestion, initiate NAC therapy and evaluate for laboratory evidence of hepatotoxicity. If evidence of hepatotoxicity exists, continue NAC therapy and consult a regional poison control center for guidance on a treatment regimen.

NAC administration in cases of hepatic failure has been associated with a decreased incidence of cerebral edema and improved survival. Therefore, NAC therapy should be initiated if concern exists for potential toxicity while awaiting confirmatory laboratory studies.

Until recently, administration of NAC to patients who presented later than 24 hours after acetaminophen ingestion was not the standard of care for acetaminophen overdose management in the United States. Data from England suggest that NAC may, in fact, be beneficial for acetaminophen-induced hepatic failure when patients present more than 24 hours after ingestion.

Currently, medical toxicologists recommend initiating treatment with NAC in patients who present more than 24 hours after ingestion, if an APAP plasma level is detected and if hepatic injury is evident from liver function studies.

The beneficial effect of NAC in late treatment, when liver damage has already occurred, suggests that additional repair mechanisms may be present. Proposed mechanisms of NAC in this setting include an antioxidant effect, decreased neutrophil accumulation, and improved microcirculatory blood flow supporting increased oxygen delivery to hepatic tissue.

Continuation of NAC therapy is based on the patient's clinical status, on detectable serum values of serum, and liver function study results. The Rumack-Matthew nomogram is not valid in cases of late presentation and should not be used to guide medical management in these cases.

Chronic Ingestion

If a patient presents after multiple ingestions or chronic ingestion of supratherapeutic doses of acetaminophen over hours or days, evaluate for the presence of a persistent serum APAP concentration and laboratory indicators of hepatotoxicity. Begin NAC therapy if the patient has elevated aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels or a measurable serum APAP concentration. Consult a regional poison control center for guidance on a treatment regimen.

Extended-Release Acetaminophen Overdose

Extended-release acetaminophen (Tylenol ER) consists of acetaminophen 325 mg in immediate release (IR) form surrounding a matrix of acetaminophen 325 mg formulated for slow release. Some alteration of the elimination kinetics of this preparation may affect the reliability of the Rumack-Matthew nomogram to predict potential hepatotoxicity and subsequent treatment based on serum APAP concentrations.

Several studies show that the elimination of ER and IR APAP preparations is nearly identical after 4 hours. However, some case reports have documented APAP levels that are above the potential toxicity and treatment line on the nomogram as late as 11-14 hours after the ingestion of the ER preparation.

Recommended management includes the measurement of 4-, 6-, and 8-hour APAP concentrations. Begin NAC therapy if any level crosses above the nomogram treatment line. If the 6-hour level is greater than the 4-hour level, begin NAC therapy. More prolonged monitoring of APAP levels may be necessary if the patient has food in his or her stomach or has taken co-ingestants that delay gastric emptying.

Consult a regional poison control center for guidance in the evaluation and optimal treatment regimen for these cases.

Consultations

Consultation with a medical toxicologist is recommended for patients who have a complicated or late presentation, hepatic or renal dysfunction, or a history of potentially toxic co-ingestants. Medical toxicologists are available through consultation with a regional poison control center. For ingestions seen as a cry for help or as an intent to self-harm, psychosocial, psychological and/or psychiatric evaluations are required.

A hepatologist, directly affiliated with a transplantation medical center, should be consulted in the setting of hepatic dysfunction and liver failure. Concurrently, consult a transplantation surgeon in the setting of clinical and laboratory indicators that are highly predictive of death unless urgent transplantation is undertaken (see Prognosis). The King's College Hospital criteria for the determination of the urgent need for transplantation after acetaminophen-induced fulminant hepatic failure include any one of the following:

Medication Summary

Activated charcoal (AC) and N -acetylcysteine (NAC) are used in the treatment of acetaminophen toxicity. Antiemetics are used to relieve nausea and vomiting, which can result from both acetaminophen toxicity and from AC and oral NAC administration.

Activated charcoal (Actidose-Aqua, EZ-Char, Kerr Insta-Char)

Clinical Context:
Activated charcoal (AC) is the drug of choice for gastric decontamination and is used for emergency treatment in poisoning caused by drugs and chemicals. A network of pores absorbs 100-1000 mg of drug per gram of charcoal. AC prevents absorption by adsorbing the drug in the intestine; multidose charcoal may interrupt enterohepatic recirculation and enhance elimination by enterocapillary exsorption.

In theory, by constantly bathing the GI tract with charcoal, the intestinal lumen serves as a dialysis membrane for reverse absorption of the drug from the intestinal villous capillary blood into the intestine. AC does not dissolve in water and for maximum effect, administer this agent within 1 hour after ingestion of poison.

N-acetylcysteine (Acetadote)

Clinical Context:
N-acetylcysteine (NAC) is the drug of choice for the prevention and treatment of APAP-induced hepatotoxicity. This medication is approved by the US Food and Drug Administration (FDA) for both oral and intravenous (IV) administration. For the maximum hepatoprotective effects, administer NAC within 8-10 hours of an acute APAP ingestion.

Three treatment protocols are recognized: 72-hour oral, 21-hour IV, and 48-hour IV. The entire NAC protocol, either oral or IV regimen, should be completed even if the acetaminophen plasma levels decrease.

When NAC is given orally, dilute this agent in chilled juice or cola to a 5% solution. Repeat the dose if vomiting occurs within 1 hour of oral administration.

The oral form, Mucomyst, is available as a 20% solution (200 mg/mL). This should be diluted to 5% solution (50 mg/mL) with fruit juice or carbonated beverage. It may be administered via nasogastric tube if severe nausea threatens administration. Aggressive antiemetic therapy is indicated in patients with nausea or vomiting due to acetaminophen-induced hepatic injury or foul sulfur odor of the solution. If the patient vomits within 60 min of administration, repeat the dose.

Class Summary

Gastrointestinal (GI) decontamination with oral AC is selectively used in the emergency treatment of poisoning caused by some drugs and chemicals. The network of pores present in AC adsorbs 100-1000 mg of drug per gram of charcoal. AC does not dissolve in water.

Consider GI decontamination with AC in any patient who presents within 1 hour after the ingestion. Maximum effect is achieved if AC is used within 1 hour post ingestion. AC may be helpful more than 4 hours post-ingestion, if co-ingestion with an agent that slows gut motility occurred or if a sustained-release preparation was ingested.

AC adsorbs acetaminophen, but its use has been controversial, because AC may absorb oral NAC. Although AC reduces the bioavailability of NAC, the small decrease in the NAC bioavailability is unlikely to reduce the effectiveness of oral NAC as an antidote.

Administer all doses of NAC as directed under the guidance of a regional poison control center. Shortened courses of NAC administration have been found to be effective in preventing liver toxicity in select patients with APAP overdose.[35, 36]

Metoclopramide (Reglan, Metozolv)

Clinical Context:
Metoclopramide functions as an antiemetic by blocking dopamine receptors in the chemoreceptor trigger zone of the central nervous system. It also enhances gastrointestinal motility and accelerates gastric emptying time. This agent is of low cost and is generally considered an initial drug of choice for the treatment of nausea.

Ondansetron (Zofran, Zuplenz)

Clinical Context:
Ondansetron is a selective 5-hydroxytryptamine (5HT3) receptor antagonist. This drug blocks serotonin by acting on the vagus nerve peripherally and at the chemoreceptor trigger zone of the central nervous system (CNS). Ondansetron is considered more effective than metoclopramide, with fewer adverse effects, but it is more costly than metoclopramide.

Class Summary

Emesis is frequently associated with APAP toxicity and is a common adverse effect of both AC and oral NAC administration. For these reasons, antiemetic therapy is often necessary to facilitate the successful administration of oral NAC. Persistent nausea or vomiting precludes oral NAC administration; in this situation, NAC should be administered intravenously.

Antiemetics that do not decrease gastric motility or significantly alter mental status are the drugs of choice; anticholinergic drugs such as prochlorperazine are not considered beneficial, in part because of their propensity to cause both of these adverse effects. Phenothiazines may also contribute to the potential toxicity associated with other anticholinergic drugs, if they are co-ingested with APAP-containing formulations.

Additional Contributors

Michael J Burns, MD is a member of the following medical societies: American Academy of Clinical Toxicology, American College of Emergency Physicians, American College of Medical Toxicology, and Society for Academic Emergency Medicine

Miguel C Fernandez, MD, FAAEM, FACEP, FACMT, FACCT is a member of the following medical societies: American Academy of Emergency Medicine, American College of Clinical Toxicologists, American College of Emergency Physicians, American College of Medical Toxicology, American College of Occupational and Environmental Medicine, Society for Academic Emergency Medicine, and Texas Medical Association

US Food and Drug Administration. June 29-30, 2009: Joint meeting of the Drug Safety and Risk Management Advisory Committee with the Anesthetic and Life Support Drugs Advisory Committee and the Nonprescription Drugs Advisory Committee: meeting announcement. Available at http://www.fda.gov/AdvisoryCommittees/Calendar/ucm143083.htm. Accessed July 11, 2013.

US Food and Drug Administration. Public health problem of liver injury related to the use of acetaminophen in both over-the-counter (OTC) and prescription (RX) products. Available at http://www.fda.gov/AdvisoryCommittees/Calendar/ucm143083.htm. Accessed June 26, 2013.

McNeil Consumer and Specialty Pharmaceuticals. Guidelines for the Management of Acetaminophen Overdose. Available at http://www.tylenolprofessional.com/assets/Overdose_Monograph.pdf. Accessed July 11, 2013.

FDA Consumer Health Information: US Food and Drug Administration. Acetaminophen and Liver Injury: Q & A for Consumers. June 2009. 1-3. Available at http://www.fda.gov/ForConsumers/ConsumerUpdates/ucm168830.htm. Accessed July 11, 2013.